TRT Impacted by Histamine Changes - Doxepin Dosage

I posted my stats recently on another thread, but a quick overview;
55yo male 6’ 175lbs
200mg test cyp - compounded with .5ml of Anastrozole -----1ml 1x/week
500 iu of HCG 2x/week

Was doing well and TT was >1500 and E2 at 23.6

Two things have occurred this week. I take Doxepin 50mg 1x/day at night for sleep. This week it was dropped to 25mg 1x/day at night. I have also noticed a notable drop in libido, energy and it’s difficult to finish during sex. I also picked up a summer cold(runny nose, sore throat ect…bs) a week ago and it’s improving.

My question is coincidence or is the the drop in doxepin changing my histamine response and also interacting with E2? I know that estrogen and histamines do a dance with each other but I’m unclear on the specifics. So is it possible that the drop in doxepin is affecting histamines which affect estrogen which is changing my TT to E2 relationship?

Any insight here would be appreciated, obviously my internist is clueless!

I’m not sure if the data you’re inquiring about exists. It’s likely that any insight you receive on this will be anecdotal.

It’s also likely that in order to verify this, you’d have to run a few sets of labs/blood work with data points of you taking the antihistamine as well as being off of it.

What’s more likely happening, is the summer cold has affected your libido. Libido is MUCH more complicated than just T/FT and e2 levels…it’s quite codependent on neurotransmitters, specifically dopamine, which can easily be hindered by getting a virus/being sick.

A quick google search did turn this up:

Question of the day: what common classs of drugs a) activates estrogen receptors, b) can increase appeitite, c) lowers acetylcholine, d) is (controversially) linked to male birth defects and e) stimulates (and potentially desensitizes) dopamine receptors? If you guessed antihistamines, you would be exactly right. If you’re like me, you didn’t read the fine print, eh?

I was alerted to the estrogen-like properties from one of my forum moderators at the time. He wrote:

“Anyone have negative experiences with antihistamines, especially loratadine? Because I’m putting the pieces together that my recent bad feelings on TRT is either due to allergies (perhaps causing more stress on already likely depleted adrenals), or allergy medication (loratadine). I’ve seen this somewhat frightening study (‘Loratadine exerts estrogen-like effects and disrupts penile development in the mouse’), and it’s not much of a leap to humans here. My guess is L caused an increase in estrogen, leading to my typical response: brain fog, fatigue, bad sleep, ED. Just a word to the wise.”" [1]

It turns out that he is kind of right: antihistamines actually activate estrogen RNA expression, i.e. you body reacts as if your plasma estrogen levels had increased. I know of no evidence that they directly increase estradiol or estrogen levels - estradiol is the most potent estrogen - but antihistamines are clearly “estrogen-like” in their properties and what they do to your body. Consider these two sobering facts about antihistamines:

  1. Increased Risk of Penile Birth Defects. One 2006 study found the following when they studied the incidence of hypospadias in women using antihistamines during pregnancy. Hypospadias is basically the placement of the opening of the penis. It’s value in this case comes from the fact that estrogens are known to effect hypospadias, i.e. cause the opening of the penis to be lower and misplaced, something that, fortunately, is usually correctictable surgically. Most importantly for this discussion, it is a great sign of estrogenic propreries:

“The adjusted odds ratio (OR) for hypospadias among users of loratadine relative to non-users was 1.4 (95% CI: 0.2-11.2) and the corresponding OR for other antihistamines was 1.9 (95% CI: 0.7-5.7). In this study, maternal exposure to loratadine did not appear to be associated with an increased risk of hypospadias when compared with other antihistamines, although it should be noted that the statistical precision of the risk estimates might be limited.” [2]

The authors were very cautious in their assessment in my opinion. Basically, they found a 40% increase with Claritin (loratidine) and 90% with other antihistamines. If you accept that at face value, not only are antihistamines esrogenic, but they can have a clincially negative effect in our littlest boys.

NOTE: Two years later another study was published about Claritin and found “only” a 27% increase is risk. The authors did not consider it statistically significant. [3]

  1. Estrogen mRNA Expression. Researchers using an animal model of hypospadias clearly found that loratidine (Claritin) was estrogenic and stated that “In utero exposure to over-the-counter loratadine syrup can result in hypospadias in this model, and creates changes in the steroid receptor mRNA expression profile similar to those elicited by a synthetic estrogen.”

CAN ANTIHISTAMINES INCREASE ESTROGEN / ESTRADIOL LEVELS? Note that the above studies do not support the idea that loratidine or other antihistamines increase actual plasma estradiol levels. Basically, these drugs increase estrogen-like effects though: your body reacts as if you had more estrogen / estradiol floating around.

That said, I would argue that they can and do definitely raise estradiol levels and the long term in a solid percentage of regular users. How? Antihistamines essentially take the brakes off of your appetite and so you put on weight. And every pound of weight that you add on increases aromatase, which in turn converts more of your testosterone to estradiol. So you could effectively end up with less testosterone and more estradiol, something I discuss in my page on Testosterone and Weight Loss.

Need some proof of the above? Check out the study results here:

“Prescription H1 antihistamine users had a significantly higher weight, waist circumference, and insulin concentration than matched controls. The odds ratio (OR) for being overweight was increased in prescription H1 antihistamine users. H1 antihistamine use may contribute to the increased prevalence of obesity and the metabolic syndrome in adults given these medications are also commonly used as over the counter remedies.” [5]

Why does this happen? It turns out that histamine reduces weight gain and appetite. [5] Again, antihistamines take the brakes off of one of the body’s natural appetite suppressants. And good luck with that in Western societies where we are drowning in food and calories!

CAUTION: The old school antihistamines, such as Benadryl, are in a class of drugs called anticholinergics. Several men on The Peak Testosterone Forum have taken these as a sleep aide. This is very risky in my opinion as these medications have been inked to an increased risk of dementia in seniors. This makes sense because acetylcholine is the memory neurotransmitter. (Acetylcholine also plays a role in erections and endothelial function.)

CONCLUSION: Now, anyone who has read my site knows what I am going to say next: instead of taking antihistamines, why not clean up your diet? True story: I was constantly plagued with allergies as a young man and young adult. I was on allergy shots for years and took antihistamines like candy. I would guess that I have easily taken several thousand pills of the stuff in the first part of my life. Furthermore, I used to be plagued with sinus infections, flus and colds - I was constantly sick.

Then something miraculous happened: I went on a whole foods, low fat, largely (at the time flexitarian) plant based diet in my late 40’s - now I am entirely plant based - and all my allergies went away. I had one particularly strong allergy to bermuda grass. If went into a park with bermuda, I would be coughing that night. This completely went away.

Remember: whole plant foods are PACKED with antiinflammatories and antioxidants. They also with a couple of exceptions (such as B12) have an excellent nutrient profile. And, most importantly, whole plant foods are PACKED with fiber - you know, the kind that your colon and your gut flora love and thrive in. The gut is ground zero for immunity, so I am not the least bit surprised myself.

Some of you will not believe me - I can scarcely believe it myself - but I never get colds or flus. I have now not had one cold or flu in the last two seasons for example. (I avoid wheat and soy myself. I feel like I feel better leaving those out.)

Anyway, not trying to offend anyone - just passing along what worked for me.



  2. Int J Med Sci, 2006, 3(1): 21�25, “Maternal use of Loratadine during pregnancy and risk of hypospadias in offspring”

  3. Drug Saf, 2008, 31(9):775-88, “Risk of hypospadias in offspring of women using loratadine during pregnancy: a systematic review and meta-analysis”

  4. J Urol, 2006 Feb;175(2):723-6, “Loratadine exerts estrogen-like effects and disrupts penile development in the mouse”

  5. Obesity (Silver Spring), 2010 Dec, 18(12):2398�2400, “Association of prescription H1 antihistamine use with obesity: Results from the National Health and Nutrition Examination Survey”

I ran across this as well:

Mayo Clin Proc. 1979 Oct;54(10):669-74.
Tricyclic antidepressants and histamine H1 receptors.
Richelson E.
Tricyclic antidepressants and some structurally related compounds were tested for their ability to antagonize histamine H1 and muscarinic acetylcholine receptors of cultured mouse neuroblastoma cells. As a group, tertiary amine tricyclic antidepressants tended to be more potent than secondary amine drugs at both receptors. The most potent antihistamine, doxepin hydrocholoride, was about 4 times more potent than amitriptyline hydrochloride, about 800 times more potent than diphenhydramine hydrochloride, and about 8,000 times more potent than desipramine hydrochloride, the least potent tricyclic antidepressant at both the histamine H1 and the muscarinic acetylcholine receptors. All tricyclic drugs except desipramine hydrochloride were more potent as antihistamines than as anticholinergics. Doxepin hydrochloride and amitriptyline hydrochloride may be the most potent antihistamines known, and the antihistaminic potencies of these and the other tricyclic antidepressant drugs may relate directly to their ability to cause sedation and drowsiness in patients.


So…given the potency of Doxepin and effectively cutting the “antihistamine” in half (50mg to 25mg) its seems as though based on above that my “body reacts as if you had more estrogen/estradiol floating around”…however I have developed and ache in the testicles that wasn’t there since the onset of TRT 4 months ago…leading me to believe T has increased telling my pituitary to shut down the testes…

Trying decipher the endocrine feeback loop, it isn’t completely making sense. My E2 was half the last lab reports when I started TRT, so if it’s being suppressed now might explain the return of lost libido even though T has risen…hypothetically…guess blood work in the current state might shed some light…

So sex/libido was good at 50mg and is not at 25mg?

Trazodone 50mg could be tried for sleep. Comes in a 150mg tab that can split to 50 or 75mg. Also time release melatonin, must be time release. Do not use fast release because it will wake you up as it wears off as falling melatonin is the mechanism of waking up.

Been on doxepin for over a decade, was just trying to cut back on the dosage to get back to the 10mg precribed by many years ago. Wasn’t expecting this kind of response. Taking no meds for the cold other than occassional Advil. Just seems out of sorts that a cold only would affect libido/sex, and testicle ache. Energy level is down but I’ll attribute that to a cold.

Had thyroid bloodwork done yesterday, will probably be back with those results to see if there are any pearls of wisdom.

Have you heard of histamine affect on E2 and seeing an effect on T?

Never, but I am not surprised that there are negative effects with long term use. I think that you need a different drug, so I made suggestions.